Abstract 667P
Background
CB307, a tri-specific Humabody targeting CD137, prostate-specific membrane antigen (PSMA), and human serum albumin, lacks an Fc domain and weighs < 50 kDa. It was designed to activate T cells exclusively in PSMA+ lesions. Preclinical studies have confirmed efficient CB307 delivery to PSMA+ tumors in mice. To understand its biodistribution, patients were imaged with PET after injection with 89-zirconium (89Zr) labeled CB307.
Methods
Patients with PSMA-positive tumors received 89Zr-CB307 (37 MBq / 5 mg protein) and escalating doses of unlabeled CB307 up to a maximum of 100 mg to achieve sufficient tracer in the circulation to allow tumor uptake. Subsequently, patients underwent 3 PET scans followed by a tumor biopsy (NCT05836623). Thereafter, patients entered the CB307 treatment trial (NCT04839991). Tracer uptake was measured as standardized uptake value in tumor lesions (SUVmax) and healthy tissues (SUVmean). Blood tracer pharmacokinetics and urine tracer concentration were assessed. Tumor biopsies were stained with hematoxylin-eosin and immunohistochemically for PSMA, and autoradiography was performed. With anti-albumin magnetic beads, the % tracer bound to albumin was assessed. Tracer integrity was determined with SDS-PAGE.
Results
Five patients were enrolled. No tracer-related adverse events were reported. One patient received 5 mg 89Zr-CB307 without unlabeled CB307, one 25 mg unlabeled CB307, and three 100 mg unlabeled CB307 with PET/CT scans at 2, 5, and 7 days (±1). The blood 89Zr-CB307 T½ was 67.1 h at 105 mg. At 105 mg, optimal tumor-to-blood ratio (10.3) occurred on day 7, and the mean tumor lesion (n=18) SUVmax was 5.8 ± SD 2.1. 89Zr-CB307 SUVmean in liver was 13.7 ± SD 1.3 and spleen 3.1 ± SD 0.4, without specific uptake in lymph nodes, bone marrow, and salivary glands. Tumor biopsies showed radioactive signal. Circulating tracer was intact and ∼100% albumin-bound, urine 89Zr-radioactivity was <2.0% of the injected dose in the 8 h post-injection, and SDS page results showed only unconjugated 89Zr in urine.
Conclusions
CB307 targets PSMA only in tumors, without specific uptake in PSMA-positive normal tissues or lymphoid tissues.
Clinical trial identification
NCT05836623.
Editorial acknowledgement
Legal entity responsible for the study
UMCG and Crescendo Biologics Ltd.
Funding
Crescendo Biologics Ltd.
Disclosure
D.G. Knapen: Financial Interests, Institutional, Local PI: Bayer. M. Lub-de Hooge: Financial Interests, Institutional, Advisory Board: Merck; Financial Interests, Institutional, Principal Investigator: Amgen, Servier. J. Pizzey: Financial Interests, Personal, Full or part-time Employment: Crescendo Biologics Ltd. R. Williams, S. Archer, P. Bland-Ward, K. Duffy, K. Hashimoto: Financial Interests, Personal, Full or part-time Employment: Crescendo Biologics Ltd; Financial Interests, Personal, Stocks or ownership: Crescendo Biologics Ltd. D.J. de Groot: Financial Interests, Institutional, Principal Investigator: F. Hoffmann-La Roche, GE; Financial Interests, Institutional, Research Grant: Amgen; Financial Interests, Institutional, Local PI: Bayer. E.G.E. de Vries: Financial Interests, Institutional, Advisory Board: NSABP, Daiichi Sankyo, Crescendo Biologics Ltd; Financial Interests, Institutional, Research Grant: Amgen, Roche; Financial Interests, Institutional, Local PI: Genentech, Bayer; Financial Interests, Institutional, Principal Investigator: Servier, Regeneron, Crescendo Biologics Ltd. All other authors have declared no conflicts of interest.
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